Investigators Grappling With Looming Disease Gene Concerns

Concerns (The Scientist, Vol:10, #6, p. 1 & 8-9, March 18, 1996) The deluge of gene discovery has inspired hundreds of industry and academic research programs to develop tests for disease genes (see accompanying story). Meanwhile, basic scientists are seeking to explain how those genes work. Both sides have been expressing concern over looming disease gene issues. Open to question, for example, is how much researchers actually know about the cellular explanation for any disease gene's effect, the reliability of a genetic test in predicting disease, and where such tests fit in the overall scheme of disease research. ACCELERATING: David Schlessinger of Washington University sees the pace of gene discovery rapidly increasing. "My sense is that we have a rudimentary understanding of how any change in a gene results in different characteristics in individuals," remarks Eric Winer, codirector of the Multidisciplinary Breast Cancer Program at Duke University. "We still don't understand what a lot of protein products are or how they work. So what do we tell people-especially those who get DNA testing-about the genetic variability and likelihood of getting a disease? How do we express our concerns?" A survey by a National Institutes of Health task force on genetic testing found that more than 450 research programs are developing genetic tests. Those tests are the topic of a public forum to be held April 29 and 30 in Baltimore. "We want to set up principles for the development of genetic tests, assure lab quality for those tests, and see that [test takers] are educated and counseled," says Neil A. Holtzman, task force chairman and a professor of pediatrics at Johns Hopkins University. "A lot of people are concerned about these issues." In 1990, genetic researchers could point to a handful of mutated genes blamed for disease. Today, disease gene discoveries come weekly. "The acceleration is extraordinary," marvels David Schlessinger, head of Washington University's Center for Genetics in Medicine, in St. Louis. "Roughly 5,000 genes have been specified to be involved in inherited disease." Since January 1995, researchers have announced discovery of genes linked to breast, colon, bladder, and ovarian cancer; Alzheimer's disease; melanoma; hypertension; and other major disorders. In the March issue of Nature Genetics, Schlessinger and colleagues add to the list, reporting the isolation of a tissue growth-regulator gene called GPC3, which, when damaged, causes an organ overgrowth disease (G. Pilia et al., Nature Genetics, 12[3]:241-7, 1996). GPC3 may also contribute to some types of cancer. "So far, only a fraction of [inherited disease genes] have been cloned," Schlessinger notes. "But that number is bound to increase. As we continue sequencing the human genome, the discoveries will come faster and faster." With disease genes in hand, many academic researchers carry a clear mission: to unravel the genes' cellular functions. This undertaking is a critical first step toward potential therapies. The month of March has brought new explanations for disease genes involving the breast and brain. In this month's issue of Nature Genetics, two related reports by collaborators at Vanderbilt University and the University of Washington in Seattle provide the first peek at the normal function of BRCA1, the much-publicized gene responsible for up to half of hereditary breast cancers (J.T. Holt et al., Nature Genetics, 12[3]:298-302, 1996; R. Jensen et al., Nature Genetics, 12[3]:303-8, 1996). In one of the experiments, researchers inserted normal and mutant human BRCA1 into a retrovirus, which was then administered to mice inoculated with tumors from human breast cancer cells. Mice receiving normal BRCA1 lived longer and experienced a better decline in tumors than their mutant BRCA1-receiving counterparts. The researchers suggest that BRCA1 is normally a tumor suppressor gene induced by pregnancy, though further studies are needed to explain the gene's action. Meanwhile, an explanation of neurological disease gene mechanics comes from collaborators at Duke and Stanford universities. Reporting in the March issue of Nature Medicine, the team explains how some so-called triple repeat genes may cause at least five neurological diseases, including Huntington's (J.R. Burke et al., Nature Medicine, 2[3]:347-50, 1996). Apparently, these genes produce proteins that bind and disable an essential energy-producing enzyme. Lacking sufficient amounts of the enzyme, brain cells malfunction and may eventually die. The work offers biomedical researchers a new way to understand and potentially treat some genetic neurological disease. Despite these high-profile studies, some scientists lament what they see as a general lag in disease gene understanding. "Today, when [researchers] have identified a particular mutation in a disease gene, we usually don't know where it goes from there," says Allen Roses, director of Duke's Center for Human Genetics and a coauthor of the triple repeat paper. "Sure, we can produce a genetic testing product. But further studies to actually explain gene function have lagged, even for monogenic diseases." Roses blames the gene-discovery-to-disease understanding gap on a lack of collaboration between cell and gene biologists. "The people who are used to dealing with genes are not the same people who deal with cell biology," he contends. "The reason we've been successful at Duke is that we are an interdisciplinary team, with a biochemist, molecular biologist, epidemiologist, immunochemist, and me." Schlessinger agrees that the team approach is essential: "To get to the molecular analysis of a gene's effect, you really need [an interdisciplinary] group. You need to know about knockout mice, in situ hybridization, clinical observation, and molecular biology analysis of protein products." One problem, both investigators say, is that most gene research funding is not designed for interdisciplinary teams. "Until now, the model has been to give significant funding to one or two people in biomedical research, while others get left out," observes Schlessinger, who, with a $12 million grant from the National Center for Human Genome Research, is mapping the sex chromosome X. Roses adds: "It's hard to do interdisciplinary research when the basic science push in this country has been to save the individual (R01) research grant." PRINCIPAL NEED: Neil Holtzman cites the need for guidelines for developing genetic tests and improving patient education. Clashing styles and egos also can prevent collaboration between disease gene fields. The race to discover and develop tests for BRCA1 and BRCA2-a second breast cancer gene-has been marked by bitter competition (G. Smith, Business Week, Dec. 4, 1995, page 109). Even within one academic medical department, crafting an interdisciplinary team is tricky, Roses points out. "When you create a group, you have to have definitions about what each person is contributing and what they get out of it. In our group, we have a hell of a lot of respect for each other." Still, despite the difficulties, Roses says, interdisciplinary teams are the future of disease gene research. "They will be the success stories," he predicts. While academic researchers struggle to grasp how genes cause disease, companies are charging ahead with tests to diagnose those genes in patients. The NIH task force has noted that most new genetic tests go without Food and Drug Administration (FDA) oversight. According to the task force's survey, at least 22 biotech companies are developing genetic tests without FDA guidance. Currently, if a company tests and uses a genetic predisposition test within its lab, FDA approval is not required. As an alternative to FDA oversight, many companies establish institutional review boards (IRBs) to guide clinical protocols. One example is Myriad Genetics Inc., a publicly owned company in Salt Lake City. Myriad plans to release a test for BRCA1 this fall. The company plans to add newly found BRCA2 to the test next year. Among other projects, Myriad is working with Bayer Corp. of Pittsburgh to develop tests for genes linked to asthma, obesity, and osteoporosis. Myriad was founded by Mark Skolnick, a geneticist currently on leave from the University of Utah and serving as the company's executive vice president for research. "Clearly, it is clinically useful for a woman to learn whether she or her family members carry a gene that increases the risk of breast cancer," says Peter Meldrum, president and CEO of Myriad. "That offers a chance to catch the disease at an early stage and perhaps reduce certain risk factors, such as lifestyle [choices] or diet." Myriad's major competitor is OncorMed, a subsidiary of Oncor Inc., a publicly owned genetic testing company in Gaithersburg, Md. OncorMed already offers the BRCA1 test to research centers and, working with physicians, tests patients for genes linked to colon and breast cancer and melanoma. Last month, Oncor-funded researchers at Johns Hopkins reported the ability to diagnose bladder cancer in 95 percent of a study's participants (L. Mao et al., Science, 271:659-62, 1996). The researchers screened for DNA markers indicating genetic instability and changes in tumor suppressor genes to make their diagnoses. According to OncorMed spokeswoman Leslie Alexandre, the company's genetic tests focus on early detection of existing disease, rather than genetic predisposition for a disease later in life. As DNA testing evolves, Meldrum envisions consumers ordering a "genetic risk profile," in which companies would run a battery of genetic tests to learn which diseases someone is most likely to contract. "That could guide health care management for that person," Meldrum says. But that kind of mass-market test upsets some consumer groups, who argue that insurance companies and employers will use such data to discriminate against disease-gene carriers. One vocal group has been Genethics, a nonprofit organization based in Hagerstown, Md., that is dedicated to fighting genetic discrimination. "What's happening, if you look at the whole thing globally, is that gene therapy so far has turned out to be a bust," declares Hans Goerl, an attorney and head of Genethics. "Now, all the genetic section of the biotech industry has got is the genes, which give them the power to predict-and precious little to do anything constructive regarding predispositions." Scientists also question the advantage of genetic tests for the general public. "Take breast cancer," notes Holtzman. "We know that two forms [BRCA1 and BRCA2] of genetic predisposition have been clearly discovered. But these forms account for less than 10 percent of all breast cancer. So for a woman without a family history of breast cancer, negative test results are virtually meaningless." What's more, researchers cannot second-guess the likelihood of cancer in women who test positive for BRCA1 or BRCA2, Winer adds. "The simple truth is that not everyone has the same disease manifestation," Winer says. "There are a lot of questions: Are there environmental influences along with disease genes that influence risk? Are there hormonal influences? How much do related genes matter? Other mutations? We just don't know." These concerns fueled a position paper by the American Society of Human Genetics (ASHG), a professional organization based in Bethesda, Md. The paper recommended that BRCA1 testing be limited to women with a strong breast-ovarian cancer history (ASHG, American Journal of Human Genetics, 55:i-iv, 1994). Pending further research, ASHG also has recommended against using the Apo-E4 gene as a test for Alzheimer's (ASHG, Journal of the American Medical Association, 274:1627-9, 1995). Regarding Alzheimer's, ASHG wrote: "Studies to date indicate that the Apo-E4 genotype alone does not provide sufficient sensitivity or specificity to allow genotyping to be used as a diagnostic test. Because [Alzheimer's] develops in the absence of Apo-E4 and because many with Apo-E4 seem to escape disease, genotyping is also not recommended for use as a predictive genetic test." Despite the uncertainties, consumers with a strong family history of diseases may indeed want to take genetic tests, and they should be allowed to, Winer maintains. But they must realize how little scientists know, he stresses. Perhaps in the end, test takers will even contribute to disease understanding, Winer notes. "When we've got people whose DNA has been tested, we might be able to conduct epidemiological studies to figure out what causes a disease to actually occur." A variety of tests may come faster with improving technology designed to spot many mutations simultaneously. Last fall, Integrated Genetics (IG), a division of publicly owned Genzyme Corp. in Framingham, Mass., announced development of a new technology: MASDA-Multiple Allele-Specific Diagnostic Assay. The assay can simultaneously comb through hundreds of patient DNA samples for known mutations. In the short term, MASDA is intended to support research at IG. But it does have the potential for diagnostics, according to Tony Shuber, a senior research scientist and manager of technology development at IG, Also touting a technology breakthrough is Affymetrix, a Santa Clara, Calif.-based biotech startup partially owned by Glaxo Wellcome plc (R.T. King, Wall Street Journal, April 11, 1995, page A1). Affymetrix's claim to fame is the GeneChip system-a microchip loaded with DNA probes that can simultaneously identify hundreds of genes or mutations. "Experiments to find mutations or genes that would normally take someone months now will take only a couple of days," says Thane Kreiner, project manager at Affymetrix. "The findings will only speed up." Of course, that means the questions will, too. Kathryn S. Brown is a freelance science writer based in Columbia, Mo.

Investigators Grappling With Looming Disease Gene Concerns

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